In preliminary studies we found that a small, recombinant adenovirus serotype 3 derived protein (Ad3K-K aka JO-1) triggers transient opening of intercellular junctions in epithelial tumors. Epithelial junctions represent physical obstacles for access and intratumoral dissemination of anti-cancer therapeutics, such as trastuzumab/Herceptin, a commercial monoclonal antibody that is used for the treatment of patients with Her2/neu-positive breast cancer. We demonstrated that JO-1 increases access to therapeutic target receptors (e.g. Her2/neu) which are trapped in epithelial junctions and significantly improves cancer therapy with monoclonal antibodies in mouse models with xenograft tumors. The goal of this proposal is to generate sufficient preclinical efficacy and safety data that allow the submission of a pre-IND application for a combination therapy of JO-1 and trastuzumab in breast cancer patients with progressing disease. Because JO-1 does not interact with murine DSG2, we will use a breast cancer model based on human DSG2-transgenic mice (DSG2/neu model).
The Specific Aims are: 1. asses JO-1 toxicity in DSG2/neu transgenic mice and find a maximal tolerated dose. 2. Study and optimize parameters for a co-therapy of JO-1 and a therapeutic monoclonal antibody (mAb) for breast cancer. 3 perform toxicity studies in non-human primates. The new co-therapeutic JO-1 has the potential to improve trastuzumab therapy. It is also relevant for cancer therapies involving adoptive T-cell therapy or liposomal chemotherapy drugs.

Public Health Relevance

The goal of this proposal is to generate sufficient preclinical efficacy and safety data that allow the submission of an IND application for a combination therapy of a recombinant epithelial junction opener and trastuzumab/Herceptin in breast cancer patients with progressing disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA144057-08S1A1
Application #
8368514
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Forry, Suzanne L
Project Start
2005-03-01
Project End
2014-11-30
Budget Start
2012-09-07
Budget End
2012-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$386,250
Indirect Cost
$136,250
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195